Solid oral dosage form containing an enhancer

ABSTRACT

The invention relates to a pharmaceutical composition and oral dosage forms comprising a bisphosphonate in combination with an enhancer to promote absorption of the bisphosphonate at the GIT cell lining. The enhancer is a medium chain fatty acid or a medium chain fatty acid derivative having a carbon chain length of from 6 to 20 carbon atoms. Preferably, the solid oral dosage form is a controlled release dosage form such as a delayed release dosage form.

This application is a Continuation-in-part of application Ser. No.09/510,560 filed Feb. 22, 2000 which claims the benefit of ProvisionalApplication No. 60/121,048 filed Feb. 22, 1999.

FIELD OF THE INVENTION

The present invention relates to a compositions and solid oral dosageforms containing an enhancer. In particular the invention relates tocompositions and solid oral dosage forms comprising a pharmaceuticallyactive ingredient in combination with an enhancer which enhances thebioavailability and/or the absorption of the active ingredient.

BACKGROUND OF THE INVENTION

The epithelial cells lining the lumenal side of the gastrointestinaltract (GIT) can be a major barrier to drug delivery via oraladministration. However, there are four recognized transport pathwayswhich can be exploited to facilitate drug delivery and transport: thetranscellular, paracellular, carrier-mediated and transcytotic transportpathways. The ability of a drug, such as a conventional drug, a peptide,a protein, a macromolecule or a nano- or microparticulate system, to“interact” with one or more of these transport pathways may result inincreased delivery of that drug from the GIT to the underlyingcirculation.

Certain drugs utilize transport systems for nutrients which are locatedin the apical cell membranes (carrier mediated route). Macromoleculesmay also be transported across the cells in endocytosed vesicles(transcytosis route). However, many drugs are transported across theintestinal epithelium by passive diffusion either through cells(transcellular route) or between cells (paracellular). Most orallyadministered drugs are absorbed by passive transport. Drugs which arelipophilic permeate the epithelium by the transcellular route whereasdrugs that are hydrophilic are restricted to the paracellular route.

Paracellular pathways occupy less than 0.1% of the total surface area ofthe intestinal epithelium. Further, tight junctions, which form acontinuous belt around the apical part of the cells, restrict permeationbetween the cells by creating a seal between adjacent cells. Thus, oralabsorption of hydrophilic drugs such as peptides can be severelyrestricted. Other barriers to absorption of drugs may includehydrolyzing enzymes in the lumen brush border or in the intestinalepithelial cells, the existence of the aqueous boundary layer on thesurface of the epithelial membrane which may provide an additionaldiffusion barrier, the mucus layer associated with the aqueous boundarylayer and the acid microclimate which creates a proton gradient acrossthe apical membrane. Absorption, and ultimately bioavailability, of adrug may also be reduced by other processes such as P-glycoproteinregulated transport of the drug back into the gut lumen and cytochromeP450 metabolism. The presence of food and/or beverages can alsointerfere with absorption and bioavailability.

Bisphosphonates are a family of drugs used to prevent and treat bonefractures, osteoporosis, Paget's disease, metastatic bone cancer, andother bone diseases with high bone resorption. Bisphosphonates bind tobone hydroxyapatite and slow down bone-eroding cells known asosteoclasts. This effect allows the bone-building cells known asosteoblasts to work more effectively.

Some of the limitations with conventional bisphosphonates includeirritation of the upper GIT, such as esophageal ulcers, and lowbioavailability. As a result, conventional bisphosphonates require aspecific dosing regimen so that the patient can absorb some of the drugproperly and avoid side effects. Because many foods, beverages,medications and calcium interfere with absorption, conventionalbisphosphonates must be administered on an empty stomach and, dependingon the particular bisphosphonate, must wait from 30 minutes to two hoursbefore consuming any food, beverages (other than water), medications orcalcium supplements. As esophageal ulcers are a known side effect,dosing regimens for conventional bisphosphonates specify that patientsconsume an entire glass of water with the dosage form and avoid assuminga horizontal orientation, such as by lying down, within 30 to 60 minutesafter administration.

The specific characteristics of alendronate served to exemplify themembers of the class of bisphosphonates and the issues associated withthem. Alendronate is a white, crystalline, odourless, non-hygroscopicbisphosphonate prepared by chemical synthesis. Alendronate monosodiumtrihydrate has a molecular weight of 325.1. Alendronate is approved inthe U.S. for the prevention and treatment of osteoporosis in men andpostmenopausal women, and for the treatment of Paget's disease of boneand glucocorticoid induced osteoporosis in both sexes. Like otherbisphosphonates, alendronate binds to bone hydroxyapatite andspecifically inhibits the activity of osteoclasts. Alendronate reducesbone turnover in human and animal models and decreases activationfrequency, reducing bone resorption in both cortical and trabecular boneand ultimately increasing bone density and strength.

The oral bioavailability of alendronate is very low and independent ofthe dose (5-80 mg), averaging 0.76% in women and 0.59% in men.Presystemic metabolism does not occur. Following oral administration ofconventional forms of alendronate, 40% of the dose absorbed is excretedin the urine within 8 hours and a further 5% is excreted over the next64 hours. Sixty to seventy per cent of the absorption occurs within 1hour of dosing. Bioavailability is markedly reduced by coincidentconsumption of food (85%-90%) and even consumption of coffee or orangejuice will impair absorption by as much as 60% or more. Coincidentmedication will also reduce absorption, as any calcium-containingcompounds and multivalent cations will bind to the bisphosphonate.Elevation of gastric pH above 6 is associated with a twofold increase inalendronate absorption. Alendronate is not metabolized and is excretedunchanged with renal clearance comparable to the glomerular filtrationrate.

Bisphosphonate compositions and oral dosage forms with improved systemicbioavailability which are not subject to the dosing restrictions ofconventional bisphosphonates would represent a considerable benefit forpatients. As a result, new strategies for delivering drugs across theGIT cell layers are needed, particularly for bisphosphonates.

Numerous potential absorption enhancers have been identified. Forinstance, medium chain glycerides have demonstrated the ability toenhance the absorption of hydrophilic drugs across the intestinal mucosa(Pharm. Res. (1994), 11, 1148-54). However, the importance of chainlength and/or composition is unclear and therefore their mechanism ofaction remains largely unknown. Sodium caprate has been reported toenhance intestinal and colonic drug absorption by the paracellular route(Pharm. Res. (1993) 10, 857-864; Pharm. Res. (1988), 5, 341-346). U.S.Pat. No. 4,656,161 (BASF AG) discloses a process for increasing theenteral absorbability of heparin and heparinoids by adding non-ionicsurfactants such as those that can be prepared by reacting ethyleneoxide with a fatty acid, a fatty alcohol, an alkylphenol or a sorbitanor glycerol fatty acid ester.

U.S. Pat. No. 5,229,130 (Cygnus Therapeutics Systems) discloses acomposition which increases the permeability of skin to a transdermallyadministered pharmacologically active agent formulated with one or morevegetable oils as skin permeation enhancers. Dermal penetration is alsoknown to be enhanced by a range of sodium carboxylates [Int. J. ofPharmaceutics (1994), 108, 141-148]. Additionally, the use of essentialoils to enhance bioavailability is known (U.S. Pat. No. 5,665,386 AvMaxInc. and others). It is taught that the essential oils act to reduceeither, or both, cytochrome P450 metabolism and P-glycoprotein regulatedtransport of the drug out of the blood stream back into the gut.

Often, however, the enhancement of drug absorption correlates withdamage to the intestinal wall. Consequently, limitations to thewidespread use of GIT enhancers are frequently determined by theirpotential toxicities and side effects. Additionally and especially withrespect to peptide, protein or macromolecular drugs, the “interaction”of the GIT enhancer with one of the transport pathways should betransient or reversible, such as a transient interaction with or openingof tight junctions so as to enhance transport via the paracellularroute.

As mentioned above, numerous potential enhancers are known. However,this has not led to a corresponding number of products incorporatingenhancers. One such product currently approved for use in Sweden andJapan is the Doktacillin™. suppository [Lindmark et al. PharmaceuticalResearch (1997), 14, 930-935]. The suppository comprises ampicillin andthe medium chain fatty acid, sodium caprate (C10).

Provision of a solid oral dosage form which would facilitate theadministration of a drug together with an enhancer is desirable. Theadvantages of solid oral dosage forms over other dosage forms includeease of manufacture, the ability to formulate different controlledrelease and extended release formulations and ease of administration.Administration of drugs in solution form does not readily facilitatecontrol of the profile of drug concentration in the bloodstream. Solidoral dosage forms, on the other hand, are versatile and may be modified,for example, to maximize the extent and duration of drug release and torelease a drug according to a therapeutically desirable release profile.There may also be advantages relating to convenience of administrationincreasing patient compliance and to cost of manufacture associated withsolid oral dosage forms.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, the compositions anddosage forms made therefrom of the present invention comprise a drug andan enhancer to promote absorption of the bisphosphonate at the GIT celllining wherein the enhancer is a medium chain fatty acid or a mediumchain fatty acid derivative having a carbon chain length of from 6 to 20carbon atoms; with the provisos that (i) where the enhancer is an esterof a medium chain fatty acid, said chain length of from 6 to 20 carbonatoms relates to the chain length of the carboxylate moiety, and (ii)where the enhancer is an ether of a medium chain fatty acid, at leastone alkoxy group has a carbon chain length of from 6 to 20 carbon atoms,and wherein the enhancer and the composition are solids at roomtemperature.

According to another aspect of the present invention, the compositionsand dosage forms made therefrom comprise a drug and an enhancer topromote absorption of the bisphosphonate at the GIT cell lining, whereinthe only enhancer present in the composition is a medium chain fattyacid or a medium chain fatty acid derivative having a carbon chainlength of from 6 to 20 carbon atoms.

In embodiments in which the drug comprises a bisphosphonate, the drugmay be selected from the group that includes alendronate, clodronate,etidronate, incadronate, ibandronate, minodronate, pamidronate,risedronate, tiludronate, zoledronate and derivatives thereof. Thebisphosphonate dosage form may be an enteric coated instant releasesolid oral dosage form which provides improved oral bioavailability andminimizes the risk of local irritation of the upper GIT. In oneembodiment, the bisphosphonate is zoledronic acid.

The dosage forms can be a tablet, a multiparticulate or a capsule. Themultiparticulate can be in the form of a tablet or contained in acapsule. The tablet can be a single or multilayer tablet havingcompressed multiparticulate in one, all or none of the layers.Preferably, the dosage form is a controlled release dosage form. Morepreferably, it is a delayed release dosage form. The dosage form can becoated with a polymer, preferably a rate-controlling or a delayedrelease polymer. The polymer can also be compressed with the enhancerand drug to form a matrix dosage form such as a controlled releasematrix dosage form. A polymer coating can then be applied to the matrixdosage form.

Other embodiments of the invention include the process of making thedosage forms, and methods for the treatment of a medical condition byadministering the dosage forms to a patient and use of a drug andenhancer in the manufacture of a medicament.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of the sodium salts of C8, C10, C12, C14, C18and C18:2 with ³H-TRH on TEER (Ωcm²) in Caco-2 monolayers at time 0 andat 30 min. intervals up to 2 hours as described in Example 1.

FIG. 2 shows the effect of the sodium salts of C8, C10, C12, C14, C18and C18:2 on P_(app) for ³H-TRH transport in Caco-2 monolayers asdescribed in Example 1.

FIG. 3 shows the serum TRH concentration-time profiles followinginterduodenal bolus dose of 500 μg TRH with NaC8 or NaC10 (35 mg)enhancer present according to the closed loop rat model described inExample 1.

FIG. 4 shows the serum TRH concentration-time profiles followinginterduodenal bolus dose of 1000 μg TRH with NaC8 or NaC10 (35 mg)enhancer present according to the closed loop rat model described inExample 1.

FIG. 5 shows the APTT response over a period of 4 hours followingadministration of USP heparin (1000 IU) with different sodium caprate(C10) levels (10 and 35 mg) according to the closed loop rat modeldescribed in Example 2.

FIG. 6 shows the anti-factor X_(a) response over a period of 5 hoursfollowing administration of USP heparin (1000 IU) in the presence ofdifferent sodium caprylate (C8) levels (10 mg and 35 mg) according tothe closed loop rat model described in Example 2.

FIG. 7 shows the anti-factor X_(a) response over a period of five hoursfollowing administration of USP heparin (1000 IU) in the presence ofdifferent sodium caprate (C10) levels (10 mg and 35 mg) according to theclosed loop rat model described in Example 2.

FIG. 8 shows the mean anti-factor X_(a) response in dogs over a periodof time up to 8 hours following administration of: a) s.c. USP heparinsolution (5000 IU); b) oral uncoated instant release tablet formulationcontaining USP heparin (90000 IU) and NaC10; c) oral uncoated instantrelease tablet formulation containing USP heparin (90000 IU) and NaC8;and d) oral uncoated sustained release tablet formulation containing USPheparin (90000 IU) and sodium caprate prepared according to theinvention as described in Example 2.

FIG. 9 shows the anti-factor X_(a) response over a period of three hoursfollowing intraduodenal administration to rats of phosphate bufferedsaline solutions of parnaparin sodium (low molecular weight heparin(LMWH)) (1000 IU), in the presence of 35 mg of different enhancers suchas sodium caprylate (C8), sodium nonanoate (C9), sodium caprate (C10),sodium undecanoate (C11), sodium laurate (C12) and different 50:50binary mixtures of enhancers, to rats (n=8) in an open loop model. Thereference product comprised administering 250 IU parnaparin sodiumsubcutaneously. The control solution comprised administering a solutioncontaining 1000 IU parnaparin sodium without any enhancerintraduodenally.

FIG. 10 shows the mean plasma levels of leuprolide over a period ofeight hours following intraduodenal administration of solutions ofleuprolide (20 mg) containing different levels of sodium caprate (0.0 g(control), 0.55 g, 1.1 g) to dogs.

FIG. 11 shows the mean anti-factor X_(a) response in dogs over a periodof eight hours following oral administration of parnaparin sodium(90,000 IU) in the presence of 550 mg sodium caprate, as both a solution(10 ml) and an instant release tablet dosage form.

FIG. 12 shows the mean anti-factor X_(a) response in humans over aperiod of 24 hours following oral administration of parnaparin sodium(90,000 IU) in the presence of sodium caprate, as both a solution (240ml) and an instant release tablet dosage form

FIG. 13 shows the mean anti-factor X_(a) response in humans over aperiod of 24 hours following intrajejunal administration of 15 mlsolutions containing different doses parnaparin sodium (20,000 IU,45,000 IU, 90,000 IU) in the presence of different doses of sodiumcaprate (0.55 g, 1.1 g, 1.65 g)

FIG. 14 shows the mean anti-factor X_(a) response in dogs over a periodof 8 hours following oral administration of 45,000 IU parnaparin sodiumas: (a) instant release capsules containing 0.55 g sodium caprate, (b)Eudragit L coated rapidly disintegrating tablets containing 0.55 gsodium caprate and (c) Eudragit L coated rapidly disintegrating tabletswithout enhancer.

FIG. 15 shows the mean anti-factor X_(a) response in dogs over a periodof 8 hours following co-administration of 45,000 IU LMWH and 0.55 gsodium caprate orally, intrajejunally and intracolonically compared tosubcutaneous administration.

FIG. 16 shows the non-dose normalized amount of alendronate excreted inthe urine over a period of 36 hours following oral administration ofalendronate (17.5 mg) with different amounts of sodium caprate (0.5 gand 0.25 g) in the fasted and fed states compared with the mean plasmalevels of Fosamax™ (35 mg) in the fasted state.

DETAILED DESCRIPTION OF THE INVENTION

As used in this specification and appended claims, the singular forms“a”, “an” and “the” include plural referents unless the content clearlydictates otherwise. Thus, for example, reference to “an enhancer”includes a mixture of two or more enhancers, reference to “a drug”includes a mixture of two or more drugs, and the like.

As used herein, the term “drug” includes any drug, includingconventional drugs and analogs thereof, appropriate for administrationvia the oral route to an animal including a human. The term “drug” alsoexplicitly includes those entities that are poorly absorbed via the oralroute including hydrophilic or macromolecular drugs such as peptides,proteins, oligosaccharides, polysaccharides or hormones including, butnot limited to, insulin, calcitonin, calcitonin gene regulating protein,atrial natriuretic protein, colony stimulating factor, betaseron,erythropoietin (EPO), interferons, somatropin, somatotropin,somatostatin, insulin-like growth factor (somatomedins), luteinizinghormone releasing hormone (LHRH), tissue plasminogen activator (TPA),thyrotropin releasing hormone (TRH), growth hormone releasing hormone(GHRH), antidiuretic hormone (ADH) or vasopressin and analogues thereofsuch as for example desmopressin, parathyroid hormone (PTH), oxytocin,estradiol, growth hormones, leuprolide acetate, goserelin acetate,naferelin, buserelin, factor VIII, interleukins such as interleukin-2,and analogues thereof and anti-coagulant agents such as heparin,heparinoids, low molecular weight heparin, hirudin and analoguesthereof, bisphosphonates including alendronate, clodronate, etidronate,incadronate, ibandronate, minodronate, pamidronate, risedronate,tiludronate and zoledronate, pentassacharides including anti-coagulantpentassacharides, antigens, adjuvants and the like. In those embodimentsin which the drug is a bisphosphonate, the drug is selected from thegroup consisting of alendronate, clodronate, etidronate, incadronate,ibandronate, minodronate, pamidronate, risedronate, tiludronate andzoledronate. As used herein, the term “drug” includes all forms thereofincluding optically pure enantiomers or mixtures, racemic or otherwise,of enantiomers as well as derivative forms such as, for example, salts,acids, esters and the like. The drug may be provided in any suitablephase state including as a solid, liquid, solution, suspension and thelike. When provided in solid particulate form, the particles may be ofany suitable size or morphology and may assume one or more crystalline,semi-crystalline and/or amorphous forms.

The drug can be included in nano- or microparticulate drug deliverysystems in which the drug is, or is entrapped within, encapsulated by,attached to, or otherwise associated with, a nano- or microparticle.

As used herein, a “therapeutically effective amount of a drug” refers toan amount of drug that elicits a therapeutically useful response in ananimal, preferably a mammal, most preferably a human.

As used herein, the term “enhancer” refers to a compound (or mixture ofcompounds) which is capable of enhancing the transport of a drug,particularly a hydrophilic and/or macromolecular drug across the GIT inan animal such as a human, wherein the enhancer is a medium chain fattyacid or a medium chain fatty acid derivative having a carbon chainlength of from 6 to 20 carbon atoms; with the provisos that (i) wherethe enhancer is an ester of a medium chain fatty acid, said chain lengthof from 6 to 20 carbon atoms relates to the chain length of thecarboxylate moiety, and (ii) where the enhancer is an ether of a mediumchain fatty acid, at least one alkoxy group has a carbon chain length offrom 6 to 20 carbon atoms. Preferably, the enhancer is a sodium salt ofa medium chain fatty acid. Most preferably, the enhancer is sodiumcaprate. In one embodiment, the enhancer is a solid at room temperature.

As used herein, the term “medium chain fatty acid derivative” includesfatty acid salts, esters, ethers, acid halides, amides, anhydrides,carboxylate esters, nitriles, as well as glycerides such as mono-, di-or tri-glycerides. The carbon chain may be characterized by variousdegrees of saturation. In other words, the carbon chain may be, forexample, fully saturated or partially unsaturated (i.e. containing oneor more carbon-carbon multiple bonds). The term “medium chain fatty acidderivative” is meant to encompass also medium chain fatty acids whereinthe end of the carbon chain opposite the acid group (or derivative) isalso functionalized with one of the above mentioned moieties (i.e., anester, ether, acid halide, amide, anhydride, carboxylate esters,nitrile, or glyceride moiety). Such difunctional fatty acid derivativesthus include for example diacids and diesters (the functional moietiesbeing of the same kind) and also difunctional compounds comprisingdifferent functional moieties, such as amino acids and amino acidderivatives, for example a medium chain fatty acid or an ester or a saltthereof comprising an amide moiety at the opposite end of the fatty acidcarbon chain to the acid or ester or salt thereof.

As used herein, a “therapeutically effective amount of an enhancer”refers to an amount of enhancer that allows for uptake oftherapeutically effective amounts of the drug via oral administration.It has been shown that the effectiveness of an enhancer in enhancing thegastrointestinal delivery of poorly permeable drugs is dependent on thesite of administration (see Examples 6, 7 and 12), the site of optimumdelivery being dependent on the drug and enhancer.

The enhancer of the present invention interacts in a transient andreversible manner with the GIT cell lining increasing permeability andfacilitating the absorption of otherwise poorly permeable molecules.Preferred enhancers include (i) medium chain fatty acids and theirsalts, (l) medium chain fatty acid esters of glycerol and propyleneglycol, and (iii) bile salts. In one embodiment, the enhancer is amedium chain fatty acid salt, ester, ether or other derivative of amedium chain fatty acid which is, preferably, solid at room temperatureand which has a carbon chain length of from 8 to 14 carbon atoms; withthe provisos that (i) where the enhancer is an ester of a medium chainfatty acid, said chain length of from 8 to 14 carbon atoms relates tothe chain length of the carboxylate moiety, and (ii) where the enhanceris an ether of a medium chain fatty acid, at least one alkoxy group hasa carbon chain length of from 8 to 14 carbon atoms. In anotherembodiment, the enhancer is a sodium salt of a medium chain fatty acid,the medium chain fatty acid having a carbon chain length of from 8 to 14carbon atoms; the sodium salt being solid at room temperature. In afurther embodiment, the enhancer is sodium caprylate, sodium caprate orsodium laurate. The drug and enhancer can be present in a ratio of from1:100000 to 10:1 (drug:enhancer) preferably, from 1:1000 to 10:1.

As used herein, the term “rate controlling polymer material” includeshydrophilic polymers, hydrophobic polymers and mixtures of hydrophilicand/or hydrophobic polymers that are capable of controlling or retardingthe release of the drug compound from a solid oral dosage form of thepresent invention. Suitable rate controlling polymer materials includethose selected from the group consisting of hydroxyalkyl cellulose suchas hydroxypropyl cellulose and hydroxypropyl methyl cellulose;poly(ethylene) oxide; alkyl cellulose such as ethyl cellulose and methylcellulose; carboxymethyl cellulose, hydrophilic cellulose derivatives;polyethylene glycol; polyvinylpyrrolidone; cellulose acetate; celluloseacetate butyrate; cellulose acetate phthalate; cellulose acetatetrimellitate; polyvinyl acetate phthalate; hydroxypropylmethyl cellulosephthalate; hydroxypropylmethyl cellulose acetate succinate; polyvinylacetaldiethylamino acetate; poly(alkylmethacrylate) and poly(vinylacetate). Other suitable hydrophobic polymers include polymers and/orcopolymers derived from acrylic or methacrylic acid and their respectiveesters, zein, waxes, shellac and hydrogenated vegetable oils.

Particularly useful in the practice of the present invention are polyacrylic acid, poly acrylate, poly methacrylic acid and poly methacrylatepolymers such as those sold under the Eudragit® trade name (Rohm GmbH,Darmstadt, Germany) specifically Eudragit® L, Eudragit® S, Eudragit® RL,Eudragit® RS coating materials and mixtures thereof. Some of thesepolymers can be used as delayed release polymers to control the sitewhere the drug is released. They include polymethacrylate polymers suchas those sold under the Eudragit® trade name (Rohm GmbH, Darmstadt,Germany) specifically Eudragit® L, Eudragit® S, Eudragit® RL, Eudragit®RS coating materials and mixtures thereof.

A solid oral dosage form according to the present invention may be atablet, a multiparticulate or a capsule. A preferred solid oral dosageform is a delayed release dosage form which minimizes the release ofdrug and enhancer in the stomach, and hence the dilution of the localenhancer concentration therein, and releases the drug and enhancer inthe intestine. A particularly preferred solid oral dosage form is adelayed release rapid onset dosage form. Such a dosage form minimizesthe release of drug and enhancer in the stomach, and hence the dilutionof the local enhancer concentration therein, but releases the drug andenhancer rapidly once the appropriate site in the intestine has beenreached, maximizing the delivery of the poorly permeable drug bymaximizing the local concentration of drug and enhancer at the site ofabsorption.

As used herein, the term “tablet” includes, but is not limited to,immediate release (IR) tablets, sustained release (SR) tablets, matrixtablets, multilayer tablets, multilayer matrix tablets, extended releasetablets, delayed release tablets and pulsed release tablets any or allof which may optionally be coated with one or more coating materials,including polymer coating materials, such as enteric coatings,rate-controlling coatings, semi-permeable coatings and the like. Theterm “tablet” also includes osmotic delivery systems in which a drugcompound is combined with an osmagent (and optionally other excipients)and coated with a semi-permeable membrane, the semi-permeable membranedefining an orifice through which the drug compound may be released.Tablet solid oral dosage forms particularly useful in the practice ofthe invention include those selected from the group consisting of IRtablets, SR tablets, coated IR tablets, matrix tablets, coated matrixtablets, multilayer tablets, coated multilayer tablets, multilayermatrix tablets and coated multilayer matrix tablets. A preferred tabletdosage form is an enteric coated tablet dosage form. A particularlypreferred tablet dosage form is an enteric coated rapid onset tabletdosage form.

As used herein, the term “capsule” includes instant release capsules,sustained release capsules, coated instant release capsules, coatedsustained release capsules, delayed release capsules and coated delayedrelease capsules. In one embodiment, the capsule dosage form is anenteric coated capsule dosage form. In another embodiment, the capsuledosage form is an enteric coated rapid onset capsule dosage form.

The term “multiparticulate” as used herein means a plurality of discreteparticles, pellets, mini-tablets and mixtures or combinations thereof.If the oral form is a multiparticulate capsule, hard or soft gelatincapsules can suitably be used to contain the multiparticulate.Alternatively a sachet can suitably be used to contain themultiparticulate. The multiparticulate may be coated with a layercontaining rate controlling polymer material. The multiparticulate oraldosage form may comprise a blend of two or more populations ofparticles, pellets, or mini-tablets having different in vitro and/or invivo release characteristics. For example, a multiparticulate oraldosage form may comprise a blend of an instant release component and adelayed release component contained in a suitable capsule. In oneembodiment, the multiparticulate dosage form comprises a capsulecontaining delayed release rapid onset minitablets. In anotherembodiment, the multiparticulate dosage form comprises a delayed releasecapsule comprising instant release minitablets. In a further embodiment,the multiparticulate dosage form comprises a capsule comprising delayedrelease granules. In yet another embodiment, the multiparticulate dosageform comprises a delayed release capsule comprising instant releasegranules.

In another embodiment, the multiparticulate together with one or moreauxiliary excipient materials may be compressed into tablet form such asa single layer or multilayer tablet. Typically, a multilayer tablet maycomprise two layers containing the same or different levels of the sameactive ingredient having the same or different release characteristics.Alternatively, a multilayer tablet may contain different activeingredient in each layer. Such a tablet, either single layered ormultilayered, can optionally be coated with a controlled release polymerso as to provide additional controlled release properties.

A number of embodiments of the invention will now be described. In eachcase the drug may be present in any amount which is sufficient to elicita therapeutic effect. As will be appreciated by those skilled in theart, the actual amount of drug compound used will depend on, among otherthings, the potency of the drug, the specifics of the patient and thetherapeutic purpose for which the drug is being used. The amount of drugcompound may suitably be in the range of from about 0.5 μg to about 1000mg. The enhancer is suitably present in any amount sufficient to allowfor uptake of therapeutically effective amounts of the drug via oraladministration. In one embodiment, the drug and the enhancer are presentin a ratio of from 1:100000 to 10:1 (drug:enhancer). In anotherembodiment, the ratio of drug to enhancer is from 1:1000 to 10:1. Theactual ratio of drug to enhancer used will depend on, among otherthings, the potency of the particular drug and the enhancing activity ofthe particular enhancer.

In one embodiment, there is provided a pharmaceutical composition and asolid oral dosage form made therefrom comprising a bisphosphonate and,as an enhancer to promote absorption of the bisphosphonate at the GITcell lining, a medium chain fatty acid or a medium chain fatty acidderivative having a carbon chain length of from 6 to 20 carbon atoms,wherein the enhancer and the composition are solids at room temperature.

In another embodiment, there is provided a pharmaceutical compositionand an oral dosage form made therefrom comprising a bisphosphonate and,as an enhancer to promote absorption of the bisphosphonate at the GITcell lining, wherein the only enhancer present in the composition is amedium chain fatty acid or a medium chain fatty acid derivative having acarbon chain length of from 6 to 20 carbon atoms.

In a further embodiment, there is provided a multilayer tabletcomprising a composition of the present invention. Typically such amultilayer tablet may comprise a first layer containing a drug and anenhancer in an instant release form and a second layer containing a drugand an enhancer in a modified release form. As used herein, the term“modified release” includes sustained, delayed, or otherwise controlledrelease of a drug upon administration to a patient. In an alternativeembodiment, a multilayer tablet may comprise a first layer containing adrug and a second layer containing an enhancer. Each layer mayindependently comprise further excipients chosen to modify the releaseof the drug or the enhancer. Thus the drug and the enhancer may bereleased from the respective first and second layers at rates which arethe same or different. Alternatively, each layer of the multilayertablet may comprise both drug and enhancer in the same or differentamounts.

In yet another embodiment, there is provided a multiparticulatecomprising a composition of the present invention. The multiparticulatemay comprise particles, pellets mini-tablets or combinations thereof,and the drug and the enhancer may be contained in the same or differentpopulations of particles, pellets or mini-tablets making up themultiparticulate. In multiparticulate embodiments, sachets and capsulessuch as hard or soft gelatin capsules can suitably be used to containthe multiparticulate. A multiparticulate dosage form may comprise ablend of two or more populations of particles, pellets or mini-tabletshaving different in vitro and/or in vivo release characteristics. Forexample, a multiparticulate dosage form may comprise a blend of animmediate release component and a delayed release component contained ina suitable capsule.

In the case of any of the above-mentioned embodiments, a controlledrelease coating may be applied to the final dosage form (capsule,tablet, multilayer tablet etc.). The controlled release coating maytypically comprise a rate controlling polymer material as defined above.The dissolution characteristics of such a coating material may be pHdependent or independent of pH.

The various embodiments of the solid oral dosage forms of the inventionmay further comprise auxiliary excipient materials such as, for example,diluents, lubricants, disintegrants, plasticizers, anti-tack agents,opacifying agents, pigments, flavorings and the like. As will beappreciated by those skilled in the art, the exact choice of excipientsand their relative amounts will depend to some extent on the finaldosage form.

Suitable diluents include for example pharmaceutically acceptable inertfillers such as microcrystalline cellulose, lactose, dibasic calciumphosphate, saccharides, and/or mixtures of any of the foregoing.Examples of diluents include microcrystalline cellulose such as thatsold under the Avicel trademark (FMC Corp., Philadelphia, Pa.) forexample Avicel™ pH101, Avicel™ pH102 and Avicel™ pH112; lactose such aslactose monohydrate, lactose anhydrous and Pharmatose DCL21; dibasiccalcium phosphate such as Emcompress® (JRS Pharma, Patterson, N.Y.);mannitol; starch; sorbitol; sucrose; and glucose. Suitable lubricants,including agents that act on the flowability of the powder to becompressed are, for example, colloidal silicon dioxide such as Aerosil™200; talc; stearic acid, magnesium stearate, and calcium stearate.Suitable disintegrants include for example lightly cross-linkedpolyvinyl pyrrolidone, corn starch, potato starch, maize starch andmodified starches, croscarmellose sodium, cross-povidone, sodium starchglycolate and combinations and mixtures thereof.

Example 1 TRH Containing Tablets

(a) Caco-2 Monolayers.

Cell Culture: Caco-2 cells were cultured in Dulbecco's Modified EaglesMedium (DMEM) 4.5 g/L glucose supplemented with 1% (v/v) non-essentialamino acids; 10% fetal calf serum and 1% penicillin/streptomycin. Thecells were cultured at 37° C. and 5% CO₂ in 95% humidity. The cells weregrown and expanded in standard tissue culture flasks and were passagedonce they attained 100% confluence. The Caco-2 cells were then seeded onpolycarbonate filter inserts (Costar; 12 mm diameter, 0.4 μm pore size)at a density of 5×10⁵ cells/cm² and incubated in six well culture plateswith a medium change every second day. Confluent monolayers between day20 and day 30 seeding on filters and at passages 30-40 were usedthroughout these studies.

Transepithelial Transport Studies: The effects of sodium salts ofvarious MCFAs on the transport of ³H-TRH (apical to basolateral flux)was examined as follows: 15.0 μCi/ml (0.2 μM) ³H-TRH was added apicallyat time zero for TRH flux experiments. The transport experiments wereperformed in Hank's Balanced Salt Solution (HBSS) containing 25 mMN-[2-hydroxyethyl]-piperazine-N′-[2-ethanesulfonic acid] (HEPES) buffer,pH 7.4 at 37° C. Due to variations in solubilities, variousconcentrations of the different MCFA sodium salts and various apicalbuffers were used as shown in Table 1. In all cases the basolateralchamber contained regular HBSS+HEPES.

TABLE 1 Concentrations and buffers used for various MCFA sodium saltsMCFA salt* Conc. (mM) Buffer NaC8:0 0.32 HBSS + HEPES NaC10:0 0.40 Ca²⁺free HBSS NaC12:0 3.77 PBS** NaC14:0 1.44 PBS** NaC18:0 0.16 HBSS +HEPES NaC18:2 0.16 HBSS + HEPES *In the nomenclature CX:Y for a MCFAsalt, X indicates the length of the carbon chain and Y indicates theposition of unsaturation, if any. **PBS—phosphate buffer solution.

After removing the cell culture medium, the monolayers were placed inwells containing prewarmed HBSS (37° C.); 1 ml apically and 2 mlbasolaterally. Monolayers were incubated at 37° C. for 30 mins. Then attime zero, apical HBSS was replaced with the relevant apical testsolution containing the radiolabelled compounds with and without theenhancer compound. Transepithelial electrical resistance (TEER) of themonolayer was measured at time zero and at 30 min intervals up to 120min using a Millicell ERS chopstix apparatus (Millipore (U.K.) Ltd.,Hertfordshire, UK) with Evom to monitor the integrity of the monolayer.The plates were placed on an orbital shaker in an incubator (37° C.).Transport across the monolayers was followed by basolateral sampling (1ml) at 30 min. intervals up to 120 mins. At each 30 min. interval eachinsert was transferred to a new well containing 2 ml fresh prewarmedHBSS. Apical stock radioactivity was determined by taking 10 μl samplesat t=0 and t=120 mins. Scintillation fluid (10 ml) was added to eachsample and the disintegrations per min. of each sample were determinedin a Wallac System 1409 scintillation counter. Mean values for ³H-TRHconcentrations were calculated for the apical and basolateral solutionsat each time point. The apparent permeability coefficients werecalculated using the method described by Artursson (Artursson P., J.Pharm. Sci. 79:476-482 (1990)).

FIG. 1 shows the effect of C8, C10, C12, C14, C18 and C18:2 sodium saltswith ³H-TRH on TEER (Ωcm²) in Caco-2 monolayers over 2 hours. The datafor the C8, C10, C14 and C18 indicate minimal reduction in TEER comparedto the control. While the data for C12 indicates some cell damage(reduction in TEER), this reduction is probably a result of the higherconcentration of enhancer used in this.

FIG. 2 shows the effect of C8, C10, C12, C14, C18 and C18:2 sodium saltson P_(app) for ³H-TRH across in Caco-2 monolayers. Compared to thecontrol, the sodium salts of C8, C10, C12 and C14 showed considerableincreases in the permeability constant, P_(app), at the concentrationsused. It is noted that the high P_(app) value observed for the C12 saltmay be indicative of cell damage at this high enhancer concentration.

Mitochondrial Toxicity Assay: Mitochondrial dehydrogenase (MDH) activitywas assessed as a marker of cell viability using a method based on thecolor change of tetrazolium salt in the presence MDH. Cells wereharvested, counted and seeded on 96 well plates at an approximatedensity of 10⁶ cells/ml (100 μl of cell suspension per well). The cellswere then incubated at 37° C. for 24 hours in humidified atmosphere, 5%CO₂. A number of wells were treated with each MCFA sodium salt solutionat the concentrations shown in Table 1 and the plate was incubated for 2hours. After incubation 10 μl of MTT labeling reagent was added to eachwell for 4 hours. Solubilization buffer (100 μl; see Table 1) was addedto each well and the plate was incubated for a further 24 hours.Absorbance at 570 nm of each sample was measured using aspectrophotometer (Dynatech MR7000).

(b) In Vivo Administration (Closed Loop Rat Model).

In vivo rat closed loop studies were modified from the methods ofDoluisio et al. (Doluisio J. T., et al: Journal of PharmaceuticalScience (1969), 58, 1196-1200) and Brayden et al. (Brayden D.: DrugDelivery Pharmaceutical News (1997) 4(1)). Male Wistar rats (weightrange 250 g-350 g) were anaesthetized with ketaminehydrochloride/acepromazine. A mid-line incision was made in the abdomenand a segment of the duodenum (7-9 cm of tissue) was isolated about 5 cmdistal from the pyloric sphincter, taking care to avoid damage tosurrounding blood vessels. The sample solutions (PBS containing C8 orC10 (35 mg) and TRH (500 μg and 1000 μg)) and control (PBS containingTRH only (500 μg and 1000 μg)) warmed to 37° C. were administereddirectly into the lumen of the duodenal segment using a 26 G needle. Allintraduodenal dose volumes (for samples and control) were 1 ml/kg. Theproximal end of the segment was ligated and the loop was sprayed withisotonic saline (37° C.) to provide moisture and then replaced in theabdominal cavity avoiding distension. The incision was closed withsurgical clips. A group of animals were administered TRH in PBS (100 μgin 0.2 ml) by subcutaneous injection as a reference.

FIG. 3 shows the serum TRH concentration-time profiles followinginterduodenal bolus dose of 500 μg TRH with NaC8 or NaC10 (35 mg)enhancer present, according to the closed loop rat model. FIG. 4 showsthe serum TRH concentration-time profiles following interduodenal bolusdose of 1000 μg TRH with NaC8 or NaC10 (35 mg) enhancer present,according to the closed loop rat model. From FIGS. 3 and 4 it can beseen that the presence of the enhancer in each case significantlyincreases the serum levels of TRH over the control TRH solutionindicating increased absorption of the drug in the presence of theenhancer.

(c) Tableting.

Having established the enhancing effect of NaC8 and NaC10 on TRH insolution, immediate release (IR) and sustained release (SR) TRH tabletsand the like may be prepared. IR and SR formulations are detailed inTables 2 and 3 below.

TABLE 2 THR IR tablet formulation details (all amounts in wt. %) SilicaMicro. TRH NaC₈ NaC10 Dioxide Mag. Stearate Lactose DisintegrantCellulose PVP 0.64 70.36 — 0.5 0.5 20 8 — — 1.27 69.73 — 0.5 0.5 20 8 —— 1.23 — 67.64 0.5 0.5 20 8 — 2.13 2.42 — 66.45 0.5 0.5 — 8 20 2.13 2.42— 66.45 0.5 0.5 20 8 — 2.13

TABLE 3 THR SR tablet formulation details (all amounts in wt. %) Micro-Silica Magnesium cystalline TRH NaC₁₀ Dioxide Stearate HPMC^((a))Cellulose PVP 1.41 77.59 0.5 0.5 20 — — 1.05 57.95 0.5 0.5 20 20 — 2.6873.94 0.5 0.5 20 — 2.37

Example 2 Heparin Containing Tablets

(a) Closed-Loop Rat Segment.

The procedure carried out in Example 1 (a) above was repeated using USPheparin in place of TRH and dosing intraileally rather thanintraduodenally. A mid-line incision was made in the abdomen and thedistal end of the ileum located (about 10 cm proximal to the ileo-caecaljunction). 7-9 cm of tissue was isolated and the distal end ligated,taking care to avoid damage to surrounding blood vessels. Heparinabsorption as indicated by activated prothrombin time (APTT) responsewas measured by placing a drop of whole blood (freshly sampled from thetail artery) on the test cartridge of Biotrack 512 coagulation monitor.APTT measurements were taken at various time points. FIG. 5 shows theAPTT response of USP heparin (1000 iu) at different sodium caprate (C10)levels (10 and 35 mg). Using APTT response as an indicator of heparinabsorption into the bloodstream, it is clear that there is a significantincrease in absorption in the presence of sodium caprate compared to thecontrol heparin solution containing no enhancer.

Citrated blood samples were centrifuged at 3000 rpm for 15 mins. toobtain plasma for anti-factor X_(a) analysis. FIG. 6 shows theanti-factor X_(a) response of USP heparin (1000 iu) in the presence ofsodium caprylate (C8, 10 mg and 35 mg). FIG. 7 shows the anti-factorX_(a) response of USP heparin (1000 iu) in the presence of sodiumcaprate (C10, 10 mg and 35 mg). The control in each case is a solutionof the same heparin concentration containing no enhancer. Thesignificant increase in anti-factor X_(a) activity observed for NaC8 (at35 mg dose) and NaC10 (at both 10 mg and 35 mg doses) is indicative ofthe increase in heparin absorption relative to the control heparinsolution.

(b) Tableting.

(i) IR Tablets.

Instant release (IR) tablets containing heparin sodium USP (197.25IU/mg, supplied by Scientific Protein Labs., Waunkee, Wis.) and anenhancer (sodium caprylate, NaC8; sodium caprate, NaC10, supplied byNapp Technologies, New Jersey) were prepared according to the formulaedetailed in Table 4 by direct compression of the blend using a Manesty(E) single tablet press. The blend was prepared as follows: heparin, theenhancer and tablet excipients (excluding where applicable colloidalsilica dioxide and magnesium stearate) were weighed out into acontainer. The colloidal silica dioxide, when present, was sievedthrough a 425 μm sieve into the container, after which the mixture wasblended for four minutes before adding the magnesium stearate andblending for a further one minute.

TABLE 4 Formulation data for IR tablets containing heparin and enhancer(all amounts in wt. %) Batch Silica Magnesium No. NaC₈ NaC₁₀ Heparindioxide stearate Mannitol Disintegrant^((a)) PVP^((b)) 1 65.7 — 13.3 0.50.5 20.0 — — 2 62.2 — 16.8 0.5 0.5 20.0 — — 3 57.49 — 21.91 0.1 0.5 20.0— — 4 75.66 — 15.34 0.5 0.5 — 8.0 — 5 — 62.0 37.5 0.5 — — — — 6 — 49.4330.07 0.5 — 20.0 — — 7 — 31.29 25.94 0.5 0.5 40.0 — 1.77 “—” indicates“not applicable” ^((a))Disintegrant used was sodium starch glycolate;^((b))PVP = polyvinyl pyrrolidone

The potency of tablets prepared above was tested using a heparin assaybased on the azure dye determination of heparin. The sample to beassayed was added to an Azure A dye solution and the heparin content wascalculated from the absorbance of the sample solution at 626 nm. Tabletdata and potency values for selected batches detailed in Table 4 aregiven in Table 5.

Dissolution profiles for IR tablets according to this Example inphosphate buffer at pH 7.4 were determined by heparin assay, sampling atvarious time points.

Heparin/sodium caprylate: Tablets from batches 1 and 2 gave rapidrelease yielding 100% of the drug compound at 15 minutes. Tablets frombatch 4 also gave rapid release yielding 100% release at 30 minutes.

Heparin/sodium caprate: Tablets from batches 5 and 6 gave rapid release100% of the drug compound at 15 minutes.

TABLE 5 Tablet data and potency values for IR heparin tablets ActualTablet Dis- heparin Potency Batch Weight Hardness integration Potency As% of No. Enhancer (mg) (N) Time(s) (mg/g) label 1 NaC₈ 431 ± 5 85 + 4 —145.675 109 2 NaC₈  414 ± 14 82 ± 9 — 175.79 105 3 NaC₈ 650 ± 4  71 ± 12552 166.4 119 4 NaC₈ 377 ± 2  58 ± 10 — 168.04 110 5 NaC₁₀  408 ± 21 79± 7 — 394.47 105 6 NaC₁₀ 490 ± 6 124 ± 10 — 323.33 108 7 NaC₁₀  584 ± 12 69 ± 22 485 143.0 102

(ii) SR Tablets.

Using the same procedure as used in (i) above, sustained release (SR)tablets were prepared according to the formulae shown in Table 6. Thepotency of controlled release tablets was determined using the sameprocedure as in (i) above. Tablet details and potency for selectedbatches are shown in Table 7.

Dissolution profiles for SR tablets according this Example weredetermined by heparin assay at pH 7.4, sampling at various time points.

Heparin/sodium caprylate: Dissolution data for batches 8, 9 and 11 areshown in Table 8. From this data it can be seen that heparin/sodiumcaprylate SR tablets with 15% Methocel K100LV with and without 5% sodiumstarch glycolate (batches 8 & 9) gave a sustained release with 100%release occurring between 3 and 4 hours. Batch 11 sustaining 10%mannitol gave a faster release.

Heparin/sodium caprate: Dissolution data for batches 13 and 14 are shownin Table 8. From this data it can be seen that heparin/sodium caprate SRtablets with 20% Methocel K100LV (batch 13) gave a sustained release ofthe drug compound over a six hour period. Where Methocel K15M (batch 14)was used in place of Methocel K100LV release of the drug compound wasincomplete after 8 hours.

TABLE 6 Formulation data for SR tablets containing heparin and enhancer(all amounts in wt. %) Batch Silica Mg. Micro. No. NaC₈ NaC¹⁰ Heparindioxide stearate HPMC^((a)) Disintegrant^((b)) Mannitol cellulosePVP^((c)) 8 69.84 — 14.16 0.5 0.5 15 — — — — 9 65.68 — 13.32 0.5 0.5 155.0 — — — 10 65.68 — 13.32 0.5 0.5 12 8.0 — — — 11 65.68 — 13.32 0.5 0.510.0 — 10.0 — — 12 53.77 — 20.48 — 1.0 14.85 — — 9.9 — 13 — 56.2 23.30.5 — 20.0 — — — — 14 — 56.2 23.3 0.5 — 20.0* — — — — 15 — 41.63 34.520.5 1.0 20.0 — — — 2.35 “—” indicates “not applicable”;^((a))Hydroxypropylmethyl cellulose: Methocel K100LV in each case except“*” in which Methocel K15M was employed; ^((b))Disintegrant used wassodium starch glycolate; ^((c))PVP = polyvinyl pyrrolidone;

TABLE 7 Table data and Potency values for SR heparin tablets ActualTablet Heparin Weight Hardness Disintegration potency Batch No. Enhancer(mg) (N) Time (s) (mg/g) 8 NaC₈ 397 ± 5  52 ± 11 — — 9 NaC₈ 436 ± 11 40± 10 — 140.08 10 NaC₈ 384 ± 4  42 ± 12 — — 11 NaC₈ 400 ± 8  72 ± 16 —129.79 12 NaC₈ 683 ± 9  84 ± 17 3318 147.10 13 NaC₁₀ 491 ± 14 69 ± 7  —— 14 NaC₁₀ 456 ± 13 47 ± 4  — — 15 NaC₁₀ 470 ± 29 — 2982 148.20

TABLE 8 Dissolution data for selected batches of SR tablets % Release(as of label) Time Batch 8 Batch 9 Batch 11 Batch 13 Batch 14 (min)(NaC₈) (NaC₈) (NaC₈) (NaC₁₀) (NaC₁₀) 0 0 0 0 0 0 15 22.9 21.2 45.3 18.85.7 30 37.3 30.8 72.3 45.0 11.6 60 57.8 54.5 101.9 44.8 11.2 120 92.290.8 109.4 65.2 20.0 240 109.5 105.8 96.4 83.1 33.9 360 — — — 90.3 66.0480 — — — 102.7 82.8

(iii) Enteric Coated Tablets.

Tablets from batches 7 and 15 were enterically coated with a coatingsolution as detailed in Table 9. Tablets were coated with 5% w/w coatingsolution using a side vented coating pan (Freund Hi-Coater).Disintegration testing was carried out in a VanKel disintegration testerVK100E4635. Disintegration medium was initially simulated gastric fluidpH1.2 for one hour and then phosphate buffer pH7. The disintegrationtime recorded was the time from introduction into phosphate buffer pH7.4to complete disintegration. The disintegration time for entericallycoated tablets from batch 7 was 34 min. 24 sec, while for enteric coatedtablets from batch 15 the disintegration time was 93 min. 40 sec.

TABLE 9 Enteric coating solution Component Amount (wt. %) Eudragit ®12.5 49.86 Diethylphthlate 1.26 Isopropyl alcohol 43.33 Talc 2.46 Water3.06

(c) Dog Study.

Tablets from batches 3, 7 and 15 in Tables 5 and 6 above were dosedorally to groups of five dogs in a single dose crossover study. Eachgroup was dosed with (1) orally administered uncoated IR tabletscontaining 90000 IU heparin and 550 mg NaC10 enhancer (batch 7); (2)orally administered uncoated IR tablets containing 90000 IU heparin and550 mg NaC8 enhancer (batch 3); (3) orally administered uncoated SRtablets containing 90000 IU heparin and 550 mg NaC10 enhancer (batch 15)and (4) s.c. administered heparin solution (5000 IU, control). Bloodsamples for anti-factor X_(a) analysis were collected from the jugularvein at various time points. Clinical assessment of all animals pre- andpost-treatment indicated no adverse effects on the test subjects. FIG. 8shows the mean anti-factor X_(a) response for each treatment, togetherwith the s.c. heparin solution reference. The data in FIG. 8 shows anincrease in the plasma anti-factor X_(a) activity for all of theformulations according to the invention. This result indicates thesuccessful delivery of bioactive heparin using both NaC8 and NaC10enhancers. Using IR formulations and an equivalent dose of heparin, alarger anti-factor X_(a) response was observed with the NaC10 enhancer,in spite of the lower dose of NaC10 relative to NaC8 administered (NaC10dose was half that of NaC8). The anti-factor X_(a) response can besustained over longer time profiles relative to IR formulations by theuse of SR tablets.

Example 3 Effect of Enhancers on the Systemic Availability of LowMolecular Weight Heparin (LMWH) after Intraduodenal Administration inRats

Male Wistar rats (250 g-350 g) were anaesthetized with a mixture ofketamine hydrochloride (80 mg/kg) and acepromazine maleate (3 mg/kg)given by intra-muscular injection. The animals were also administeredwith halothane gas as required. A midline incision was made in theabdomen and the duodenum was isolated.

The test solutions, comprising parnaparin sodium (LMWH) (Opocrin SBA,Modena, Italy) with or without enhancer reconstituted in phosphatebuffered saline (pH 7.4), were administered (1 ml/kg) via a cannulainserted into the intestine approximately 10-12 cm from the pyloris. Theintestine was kept moist with saline during this procedure. Followingdrug administration, the intestinal segment was carefully replaced intothe abdomen and the incision was closed using surgical clips. Theparenteral reference solution (0.2 ml) was administered subcutaneouslyinto a fold in the back of the neck.

Blood samples were taken from a tail artery at various intervals andplasma anti-factor X_(a) activity was determined. FIG. 9 shows the meananti-factor X_(a) response over a period of 3 hours followingintraduodenal administration to rats of phosphate buffered salinesolutions of parnaparin sodium (LMWH) (1000 IU), in the presence of 35mg of different enhancers [sodium caprylate (C8), sodium nonanoate (C9),sodium caprate (C10), sodium undecanoate (C11), sodium laurate (C12)]and different 50:50 binary mixtures of enhancers, to rats (n=8) in anopen loop model. The reference product comprised administering 250 IUparnaparin sodium subcutaneously. The control solution comprisedadministering a solution containing 1000 IU parnaparin sodium withoutany enhancer intraduodenally.

FIG. 9 shows that the systemic delivery of LMWH in the absence ofenhancer is relatively poor after intraduodenal administration to rats;however, the co-administration of the sodium salts of medium chain fattyacids significantly enhanced the systemic delivery of LMWH from the ratintestine

Example 4 Effect of Enhancers on the Systemic Availability of Leuprolideafter Intraduodenal Administration in Dogs

Beagle dogs (10-15 Kg) were sedated with medetomidine (80 μg/kg) and anendoscope was inserted via the mouth, esophagus and stomach into theduodenum. The test solutions (10 ml), comprising leuprolide acetate(Mallinckrodt Inc, St. Louis, Mo.) with or without enhancerreconstituted in deionized water were administered intraduodenally viathe endoscope. Following removal of the endoscope, sedation was reversedusing atipamezole (400 μg/kg). The parenteral reference solutionscomprising 1 mg Leuprolide reconstituted in 0.5 ml sterile water wereadministered intravenously and subcutaneously respectively.

Blood samples were taken from the jugular vein at various intervals andplasma leuprolide levels were determined. The resulting mean plasmaleuprolide levels are shown in FIG. 10. The results show that, althoughthe systemic delivery of leuprolide when administered intraduodenallywithout enhancer is negligible, coadministration with enhancer resultedin a considerable enhancer dose dependent enhancement in the systemicdelivery of leuprolide; a mean % relative bioavailability of 8% observedfor at the upper dose of enhancer.

Example 5 Effect of Enhancers on the Systemic Availability of LMWH afterOral Administration in Dogs

(a) Granulate Manufacture

A 200 g blend containing parnaparin sodium (47.1%), sodium caprate(26.2%), mannitol (16.7%) and Explotab™ (Roquette Freres, Lestrem,France) (10.0%) was granulated in a Kenwood Chef mixer using water asthe granulating solvent. The resulting granulates were tray dried in anoven at 67-68° C. and size reduced through 1.25 mm, 0.8 mm and 0.5 mmscreens respectively in an oscillating granulator. The actual potency ofthe resulting granulate was determined as 101.1% of the label claim.

(b) 30,000 IU LMWH/183 mg Sodium Caprate Instant Release TabletManufacture

The granulate described above was bag blended with 0.5% magnesiumstearate for 5 minutes. The resulting blend was tableted using 13 mmround concave tooling on a Riva Piccalo tablet press to a target tabletcontent of 30,000 IU parnaparin sodium and 183 mg sodium caprate. Thetablets had a mean tablet hardness of 108 N and a mean tablet weight of675 mg. The actual LMWH content of the tablets was determined as 95.6%of label claim.

Disintegration testing was carried out on the tablets. One tablet wasplaced in each of the six tubes of the disintegration basket. Thedisintegration apparatus was operated at 29-30 cycles per minute usingde-ionized water at 37° C. Tablet disintegration was complete in 550seconds.

(c) 90,000 IU LMWH/0.55 g Sodium Caprate Solution Manufacture

90,000 IU parnaparin sodium and 0.55 g sodium caprate were individuallyweighed into glass bottles and the resulting powder mixture wasreconstituted with 10 ml water.

(d) Dog Biostudy Evaluation

90,000 IU parnaparin sodium and 550 mg sodium caprate was administeredas both a solution dosage form (equivalent to 10 ml of the abovesolution composition) and a fast disintegrating tablet dosage form(equivalent to 3 tablets of the above tablet composition) in a singledose, non randomized, cross-over study in a group of six female beagledogs (9.5-14.4 Kg) with a seven day washout between treatments. Asubcutaneous injection containing 5000 IU parnaparin sodium was used asthe reference.

Blood samples were taken from the jugular vein at various intervals andanti-factor X_(a) activity was determined. Data was adjusted forbaseline anti-factor X_(a) activity. The resulting mean plasmaanti-factor X_(a) levels are summarized in FIG. 11. Both the tablet andsolution dosage forms showed good responses when compared with thesubcutaneous reference leg. The mean delivery, as determined by plasmaantifactor X_(a) levels, of parnaparin sodium from the solid dosage formwas considerably greater than that from the corresponding solutiondosage form.

Example 6 Effect of Enhancers on the Systemic Availability of LMWH afterOral Administration in Humans

(a) Granulate Manufacture

Parnaparin sodium (61.05%), sodium caprate (33.95%) and polyvinylpyrrolidone (Kollidon 30, BASF AG, Ludwigshafen, Germany) (5.0%) weremixed for 5 minutes in a Gral 10 prior to the addition of water, whichwas then gradually added, with mixing, using a peristaltic pump untilall the material was apparently granulated.

The resultant granulates were tray dried in an oven at either 50° C. for24 hours. The dried granules were milled through a 30 mesh screen usinga Fitzmill M5A

(b) 45,000 IU LMWH/275 mg Sodium Caprate Instant Release TabletManufacture

The parnaparin sodium/sodium caprate/polyvinyl pyrrolidone granulate(78.3%) was blended for 5 minutes with mannitol (16.6%), Explotab (5.0%)and magnesium stearate (1.0%) in a 10 liter V Cone blender. The potencyof the resulting blend (480.41 mg/g) was 100.5% of the label claim. Theblend was tableted using 13 mm round normal concave tooling on thePiccola 10 station press in automatic mode to a target content of 45,000IU LMWH and 275 mg sodium caprate. The resulting instant release tabletshad a mean tablet weight of 1027 mg, a mean tablet hardness of 108 N anda potency of 97% label claim. The tablets showed a disintegration timeof up to 850 seconds and 100% dissolution into pH 1.2 buffer in 30minutes.

(c) 90,000 IU LMWH/550 mg Sodium Caprate Solution Manufacture

Two instant tablets, each containing 45,000 IU LMWH and 275 mg sodiumcaprate, were reconstituted in 30 ml water.

(d) Human Biostudy Evaluation

90,000 IU LMWH and 550 mg sodium caprate was orally administered to 12healthy human volunteers as both a solution dosage form (equivalent to30 ml of the above solution dosage form) and as a solid dosage form(equivalent to 2 tablets of the above composition) in an open label,three treatment, three period study with a seven day washout betweeneach dose; Treatments A (Instant Release Tablets) and B (Oral Solution)were crossed over in a randomized manner whereas Treatment C (6,400 IUFluxum™ SC (Hoechst Marion Roussel), a commercially available injectableLMWH product) was administered to the same subjects as a single block.

Blood samples were taken at various intervals and anti-factor X_(a)activity was determined. The resulting mean anti-factor X_(a) levels areshown in FIG. 12. Treatments A and B exhibited unexpectedly lowresponses when compared with the subcutaneous reference treatment.However it should be noted that the mean delivery of LMWH, as measuredby plasma anti-factor X_(a) levels, was considerably higher from thesolid dosage form than that from the corresponding solution dosage formfor which a mean % bioavailability of only 0.9% was observed.

Example 7 Effect of Enhancers on the Systemic Availability of LMWH afterIntrajejunal Administration in Humans

(a) Solution Manufacture

The following LMWH/sodium caprate combinations were made with 15 mldeionized water:

(i) 20,000 IU LMWH, 0.55 g Sodium Caprate;

(ii) 20,000 IU LMWH, 1.1 g Sodium Caprate;

(iii) 45,000 IU LMWH, 0.55 g Sodium Caprate;

(iv) 45,000 IU LMWH, 1.1 g Sodium Caprate;

(v) 45,000 IU LMWH, 1.65 g Sodium Caprate.

(b) Human Biostudy Evaluation

15 ml of each of the above solutions was administered intrajejunally viaa nasojejunal intubation in an open label, six treatment periodcrossover study in up to 11 healthy human volunteers. 3,200 IU Fluxum™SC was included in the study as a subcutaneous reference. Blood sampleswere taken at various intervals and anti-factor X_(a) activity wasdetermined. The resulting mean anti-factor X_(a) levels are shown inFIG. 13.

It should be noted that the mean % relative bioavailability for eachtreatment in the current study was considerably higher than the mean %bioavailability observed for the solution dosage form in Example 6; mean% bioavailabilities ranging from 5% to 9% were observed for thetreatments in the current study suggesting that the preferred LMWH oraldosage form containing sodium caprate should be designed to minimizerelease of drug and enhancer in the stomach and maximize the release ofdrug and enhancer in the small intestine.

Example 8 Manufacture of Delayed Release Tablet Dosage Form ContainingLMWH and Enhancer

(a) LMWH/Sodium Caprate Granulate Manufacture

A 500 g batch of parnaparin sodium:sodium caprate (0.92:1) wasgranulated in a Gral 10 using a 50% aqueous solution of Kollidon 30 asthe granulating solvent. The resulting granulate was dried for 60minutes in a Niro Aeromatic Fluidized Bed Drier at a final producttemperature of 25° C. The dried granulate was milled through a 30 meshscreen in a Fitzmill M5A. The potency of the resulting dried granulatewas determined as 114.8% of the label claim.

(b) 22,500 IU LMWH/275 mg Sodium Caprate Instant Release TabletManufacture

The above granulate (77.5%) was added to mannitol (16%), Polyplasdone™XL (ISP, Wayne, N.J.) (5%) and Aerosil™ (1%) (Degussa, Rheinfelden,Germany) in a 10 IV coned blender and blended for 10 minutes. Magnesiumstearate (0.5%) was added to the resulting blend and blending wascontinued for a further 3 minutes. The resulting blend was tableted onPiccola tablet press using 13 mm round normal concave tooling to a meantablet weight of 772 mg and a mean tablet hardness of 140 N.

The actual potency of the resulting tablets was determined as 24,017 IULMWH per tablet.

(c) 22,500 IU LMWH/275 mg Sodium Caprate Delayed Release TabletManufacture

The above tablets were coated with a coating solution containingEudragit L 12.5 (50%), isopropyl alcohol (44.45%), dibutyl sebecate(3%), talc (1.3%), water (1.25%) in a Hi-Coater to a final % weight gainof 5.66%.

The resulting enteric coated tablets remained intact after 1 hourdisintegration testing in pH 1.2 solution; complete disintegration wasobserved in pH 6.2 medium after 32-33 minutes.

Example 9 Manufacture of Instant Release Capsule Dosage Form ContainingLMWH and Enhancer

(a) 22,500 IU LMWH/275 mg Sodium Caprate Instant Release CapsuleManufacture

The granulate from the previous example, part a, was hand filled intoSize 00 hard gelatin capsules to a target fill weight equivalent to thegranulate content of the tablets in the previous example.

Example 10 Manufacture of Delayed Release Tablet Dosage Form ContainingLMWH without Enhancer

(a) LMWH Granulate Manufacture

A 500 g batch of parnaparin sodium: Avicel™ pH 101 (0.92:1) (FMC, LittleIsland, Co. Cork, Ireland) was granulated in a Gral 10 using a 50%aqueous solution of Kollidon 30 as the granulating solvent. Theresulting granulate was dried for 60 minutes in a Niro AeromaticFluidized Bed Drier at an exhaust temperature of 38° C. The driedgranulate was milled through a 30 mesh screen in a Fitzmill M5A. Thepotency of the resulting dried granulate was determined as 106.5% of thelabel claim.

(b) 22,500 IU LMWH Instant Release Tablet Manufacture

The above granulate (77.5%) was added to mannitol (21%) and Aerosil (1%)in a 25 L V coned blender and blended for 10 minutes. Magnesium stearate(0.5%) was added to the resulting blend and blending was continued for afurther 1 minute. The resulting blend was tableted on Piccola tabletpress using 13 mm round normal concave tooling to a mean tablet weightof 671 mg and a mean tablet hardness of 144 N.

The actual potency of the resulting tablets was determined as 21,651 IULMWH per tablet.

(c) 22,500 IU LMWH Delayed Release Tablet Manufacture

The above tablets were coated with a coating solution containingEudragit L 12.5 (50%), isopropyl alcohol (44.45%), dibutyl sebecate(3%), talc (1.3%) and water (1.25%) in a Hi-Coater to a final % weightgain of 4.26%.

The resulting enteric coated tablets remained intact after 1 hourdisintegration testing in pH 1.2 solution; complete disintegration wasobserved in pH 6.2 medium in 22 minutes.

Example 11 Effect of Controlled Release Dosage Form Containing Enhanceron the Systemic Availability of LMWH after Oral Administration in Dogs

(a) Dog Study Evaluation

45,000 IU LMWH was administered to 8 beagle dogs (10.5-13.6 Kg), in anopen label, non randomized crossed over block design, as (a) an instantrelease capsule dosage form containing 550 mg sodium caprate (equivalentto 2 capsules manufactured according to Example 9) (b) a delayed releasetablet dosage containing 550 mg sodium caprate (equivalent to twotablets manufactured according to Example 8) and (c) a delayed releasetablet dosage not containing any enhancer (equivalent to 2 tabletsmanufactured according to Example 10). 3,200 IU Fluxum™ SC was includedin the study as a subcutaneous reference. Blood samples were taken fromthe jugular vein at various intervals and anti-factor X_(a) activity wasdetermined. The resulting mean anti-factor X_(a) levels are shown inFIG. 14.

It should be noted that in the absence of sodium caprate, the systemicdelivery of LMWH was minimal from the delayed release solid dosage formwithout enhancer. In contrast, a good anti-factor X_(a) response wasobserved after administration of the delayed release LMWH solid dosageform containing sodium caprate. The mean anti-factor X_(a) response fromthe delayed release dosage form containing sodium caprate wasconsiderably higher than that from the instant release dosage formcontaining the same level of drug and enhancer.

Example 12 Effect of the Site of Administration on the SystemicAvailability of LMWH in Dogs after Co-administration with Enhancer

Four beagle dogs (10-15 Kg) were surgically fitted with catheters to thejejunum and colon respectively. The test solutions (10 ml) comprisingLMWH with sodium caprate reconstituted in deionized water wereadministered to the dogs either orally or via the intra-intestinalcatheters. 3,200 IU Fluxum™ SC was included in the study as asubcutaneous reference. Blood samples were taken from the brachial veinat various intervals and anti-factor X_(a) activity was determined. Theresulting mean anti-factor X_(a) levels are shown in FIG. 15. Theresults show that the intestinal absorption of LMWH in the presence ofenhancer is considerably higher than absorption from the stomach.

Example 13 Leuprolide Containing Tablets

Following the same type of approach as used in Examples 1 and 2,leuprolide-containing IR tablets may be prepared according to theformulations detailed in Table 10.

Example 14 Intrajejunal Administration of Alendronate

A study was conducted as an open labeled, randomized, 7 treatment, 6period study with IJ or PO administrations and at least a 48 hourwashout period between each dose. Nineteen (19) healthy male subjectswere enrolled into the study and the 15 subjects who were dosed at leastonce were included in the pharmacokinetic analysis. Pharmacokineticanalysis was based on urinary excretion of alendronate. Table 11 showsthe treatments, cumulative amount and % of administered dose excreted inthe urine (based on the cumulative amount) in this study.

TABLE 11 MEAN PK PARAMETERS (MEAN ± SD − CV %) % of Administered Doseexcreted Cumulative Treatment In the urine(%) Amount (mg) 10 mgFosamax ™ 0.61 ± 1.11 0.06 ± 0.11 (CV %) 181.3  181.3  10 mgAlendronate + 0.25 g 3.77 ± 3.16 0.38 ± 0.32 C10 (IJ) (CV %) 83.9 83.910 mg Alendronate + 0.50 g 6.64 ± 4.97 0.66 ± 0.50 C10 (IJ) (CV %) 74.974.9 10 mg Alendronate + 0.75 g 7.66 ± 3.72 0.77 ± 0.37 C10 (IJ) (CV %)48.6 48.6 70 mg Alendronate + 0.75 g 10.47 ± 3.63  7.33 ± 2.54 C10 (IJ)(CV %) 34.7 34.7

As shown by these data, the gastrointestinal absorption of alendronatewas significantly enhanced when administered as an intrajejunal bolussolution with sodium caprate, compared to the current commerciallyavailable uncoated instant release Fosamax™ reference tablet.

Example 15 Intrajejunal and Oral Administration of Alendronate

In an open label, partially randomized, 3 treatment, 3 period study withat least a 48 hour washout between each dose, twelve (12) male subjectswere dosed at least once during the course of the study and wereincluded in the pharmacokinetic analysis. The following treatments wereadministered in this study:

TABLE 12 MEAN PK PARAMETERS (MEAN ± SD − CV %) Treatments Trt A Trt B17.5 mg 17.5 mg Alendronate + Alendronate + Trt C 0.5 g C10 1.1 g C10 35mg (IJ Infusion over (IJ Infusion over Fosamax ™ PK 25 min) 25 min) (PO)Parameters n12 n12 n12 Relative 3376.78 ± 5362.54 2664.30 ± 2183.57 —Bioavailability (%) (CV %) 158.8  82.0 — Cumulative 0.89 ± 0.71 1.20 ±0.74 0.21 ± 0.31 Amount (mg) (CV %) 80.0 61.5 149.4 % of 5.08 ± 4.076.88 ± 4.23 0.59 ± 0.88 Administered Dose Excreted in the Urine (CV %)80.0 61.5 149.4

As shown by these data, the systemic absorption of alendronate wasconsiderably enhanced after co-administration, as an aqueousintrajejunal infusion (over 25 minutes), with sodium caprate. Thisfinding indicates that an enteric coated instant release oral dosageform of alendronate and C10, with enhanced oral absorption ofalendronate, as compared to the currently commercially available dosageform, should be advantageous.

Example 16 Oral Administration of Alendronate

A study was conducted to compare the relative bioavailability ofalendronate administered as solid oral dosage forms containing anabsorption enhancer, with an oral dose of the commercially availablereference dosage form Fosamax™. This study was conducted as an openlabel, partially randomized, single dose, 5 treatment, 5 period studywith at least a 48 hour washout between each dose. Sixteen (16) healthyvolunteers (13 male and 3 female subjects between 20 and 34 years oldand weighing between 64.1 and 81.5 kg) were enrolled and completed all 5treatments as set forth in Table 13 below.

TABLE 13 Treatment ID n Route Treatment Trt A 16 PO 35 mg of Fosamax ™(Merck Sharp & Dohme Ltd.) administered as 1 tablet with 250 mL tapwater Fasted Trt B 16 PO 17.5 mg Alendronate and 0.5 g C10 administeredas 2 tablets with 250 mL tap water (8.75 mg Alendronate and 0.25 g C10per tablet) Fasted HPMC P-55/Opadry coated alendronate/C10 tablets Trt C16 PO 17.5 mg Alendronate and 0.5 g 010 administered as 2 tablets with250 mL tap water (8.75 mg Alendronate and 0.25 g C10 per tablet) Fed(High Fat) HPMC P-55/Opadry coated alendronate/C10 tablets Trt D 16 PO17.5 mg Alendronate and 0.25 g C10 administered as 2 tablets with 250 mLtap water (8.75 mg Alendronate and 0.125 g C10 per tablet) Fasted HPMCP-55 I Opadry coated alendronate/C10 tablets Trt E 16 PO 17.5 mgAlendronate and 0.25 g C10 administered as 1 tablet with 250 mL tapwater (17.5 mg Alendronate and 0.25 g C10 per tablet) Fasted HPMCP-55/Opadry coated alendronate/C10 tablets

Human urine samples were collected across a 36-hour sampling period andanalyzed by HPLC with fluorescence detection (assay range: 2 to 2000ng/mL). The mean % of administered dose excreted in the urine (based onthe cumulative amount) for the test treatments, were as follows:

TABLE 14 % of Administered Dose Excreted in the Urine Treatment ID (CV%) Trt A 0.3 ± 0.1 (33.6) Trt B 1.5 ± 0.6 (40.5) Trt C 0.2 ± 0.2 (109.8)Trt D 1.6 ± 1.7 (106.8) Trt E 1.2 ± 0.9 (79.0)

Paired t-test analysis was conducted comparing the % Dose Excreted ofthe test prototypes versus % Dose Excreted for Fosamax™.

TABLE 17 Treatment Trt A Significance P-Value Trt B S Higher <0.001Significance level less than the 0.1% Trt C S Lower 0.037 Significancelevel 5% Trt D S Higher 0.006 Significance level 1% Trt E S Higher 0.001Significance level 1% S = Statistically significant

A statistically significant increase in the % of the administered doseof alendronate excreted in the urine was observed for the testprototypes administered fasted (dosed as 1 or 2 tablets) compared tothat observed for the reference product, Fosamax™. A statisticallysignificant decrease in the percent of the administered dose ofalendronate excreted was observed for the test prototype administeredfed (Trt C—sig. at 5%) as compared to that observed for Fosamax™. Thecumulative amount of administered dose recovered in the urine for thetest administrations was 4.6-6.4-fold greater than that observed forFosamax™.

Increasing the amount of C10 co-administered with alendronate from 0.25g to 0.5 g did not change the % of administered dose recovered in theurine (1.6±1.7% and 1.5±0.6% respectively). The administration of 17.5mg alendronate with 0.25 g C10 as 2 tablets (Trt D) resulted in a higher% of administered dose recovered of alendronate (1.6±1.7%) than whenadministered as 1 tablet according to Trt E (1.2±0.9%). When 17.5 mgalendronate and 0.5 g C10 was administered as 2 tablets in the fed state(Trt C), 0.2±0.2% of alendronate was determined in the urine. It shouldbe noted that the published literature states that the bioavailabilityof Fosamax™ is negligible when alendronate is administered with or up to2 hours after a standard breakfast.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and accompanyingfigures. Such modifications are intended to fall within the scope of theappended claims.

We claim:
 1. A solid oral dosage form comprising a pharmaceuticalcomposition consisting of: (a) a therapeutically effective amount of abisphosphonate selected from the group consisting of alendronate,clodronate, etidronate, incadronate, ibandronate, minodronate,pamidronate, risedronate, tiludronate and zoledronate; (b) atherapeutically effective amount of one or more enhancers, each of whichis a salt of a medium chain fatty acid having a carbon chain length offrom 8 to 14 carbon atoms and is a solid at room temperature, whereinthe one or more enhancers promote absorption of the bisphosphonate atthe gastrointestinal tract cell lining; and (c) one or more excipientsselected from the group consisting of rate-controlling polymericmaterials, diluents, lubricants, disintegrants, plasticizers, anti-tackagents, opacifying agents, pigments, and flavorings.
 2. The solid oraldosage form of claim 1 wherein the enhancer is a sodium salt of a mediumchain fatty acid.
 3. The solid oral dosage form of claim 2, wherein theenhancer is selected from the group consisting of sodium caprylate,sodium caprate and sodium laurate.
 4. The solid oral dosage form ofclaim 1, wherein the bisphosphonate is alendronate.
 5. The solid oraldosage form of claim 1, wherein the bisphosphonate is clodronate.
 6. Thesolid oral dosage form of claim 1, wherein the bisphosphonate isetidronate.
 7. The solid oral dosage form of claim 1, wherein thebisphosphonate is incadronate.
 8. The solid oral dosage form of claim 1,wherein the bisphosphonate is ibandronate.
 9. The solid oral dosage formof claim 1, wherein the bisphosphonate is minodronate.
 10. The solidoral dosage form of claim 1, wherein the bisphosphonate is pamidronate.11. The solid oral dosage form of claim 1, wherein the bisphosphonate isrisedronate.
 12. The solid oral dosage form of claim 1, wherein thebisphosphonate is tiludronate.
 13. The solid oral dosage form of claim1, wherein the bisphosphonate is zoledronate.
 14. The solid oral dosageform of claim 1, wherein the solid oral dosage form is in the form of atablet, a capsule or a multiparticulate.
 15. The solid oral dosage formof claim 1, wherein the dosage form is a delayed release dosage form.16. The solid oral dosage form of claim 1, wherein the solid oral dosageform is in the form of a tablet.
 17. The solid oral dosage form of claim8, wherein the tablet is a multilayer tablet.
 18. The solid oral dosageform of claim 1, wherein the dosage form comprises a rate-controllingpolymer material.
 19. The dosage form of claim 18, wherein therate-controlling polymer material is hydroxypropyl-methylcellulose. 20.The solid oral dosage form of claim 18, wherein the rate-controllingpolymer material is a polymer derived from acrylic or methacrylic acidand their respective esters or copolymers derived from acrylic ormethacrylic acid and their respective esters.
 21. The solid oral dosageform of claim 18, wherein the dosage form is compressed into a tabletform prior to coating with the rate-controlling polymer material. 22.The solid oral dosage form of claim 21, wherein the tablet is amultilayer tablet.
 23. The solid oral dosage form of claim 1, whereinthe solid oral dosage form is in the form of a multiparticulate.
 24. Thesolid oral dosage form of claim 23, wherein the multiparticulatecomprises discrete particles, pellets, minitablets, or combinationsthereof.
 25. The solid oral dosage form of claim 24, wherein themultiparticulate comprises a blend of two or more populations ofparticles, pellets, minitablets, or combinations thereof havingdifferent in vitro or in vivo release characteristics.
 26. The solidoral dosage form of claim 23, wherein the multiparticulate isencapsulated in a hard or soft gelatin capsule.
 27. The solid oraldosage form of claim 26, wherein the capsule is coated with therate-controlling polymer material.
 28. The solid oral dosage form ofclaim 23, wherein the multiparticulate is incorporated into a sachet.29. The solid oral dosage form of claim 24, wherein the discreteparticles, pellets, minitablets, or combinations thereof are compressedinto a tablet.
 30. The solid oral dosage form of claim 29, wherein thetablet is coated with a rate controlling polymer material.
 31. The solidoral dosage form of claim 29, wherein the tablet is a multilayer tablet.32. The solid oral dosage form of claim 30 wherein the tablet is amultilayer tablet.
 33. The solid oral dosage form of claim 1 wherein thebisphosphonate and the enhancer are present in a ratio of from 1:100,000to 10:1 (drug:enhancer).
 34. The solid oral dosage form of claim 33,wherein the ratio is from 1:1,000 to 10:1 (drug:enhancer).
 35. The solidoral dosage form of claim 1 comprising about 0.5 μg to about 1,000 mg ofdrug.
 36. The solid oral dosage form of claim 1, wherein the solid oraldosage form is in the form of a delayed release enteric coated tablet.37. The solid oral dosage form of claim 36, wherein the bisphosphonateand the enhancer are present in a ratio of from 1:1,000 to 10:1(drug:enhancer).
 38. The solid oral dosage form of claim 36, wherein theenhancer is sodium caprate.
 39. A process for the manufacture of a solidoral dosage form comprising the steps of: a) providing a blendconsisting of: (i) a bisphosphonate; (ii) one or more enhancers topromote absorption of the bisphosphonate at the GIT cell lining, whereineach enhancer is a salt of a medium chain fatty acid having a carbonchain length of from 8 to 14 carbon atoms and is a solid at roomtemperature; and (iii) one or more excipients selected from the groupconsisting of rate-controlling polymeric materials, diluents,lubricants, disintegrants, plasticizers, anti-tack agents, opacifyingagents, pigments, and flavorings; and b) forming the solid oral dosageform from the blend by: i) directly compressing the blend; or ii)granulating the blend to form a granulate for incorporation into saidsolid oral dosage form.
 40. The process of claim 38 wherein the drug andthe enhancer are blended in a ratio of from 71:100,000 to 10:1(drug:enhancer).